Method for producing 4-methyl pyrimidine

ABSTRACT

A process is described for preparing 4-methylpyrimidine by reacting a 4,4-dialkoxy-2-butanone with a formamidine salt, optionally in the presence of a solvent or diluent, at temperatures of from 80 to 180° C. In this way, 4-methylpyrimidine can be obtained in a substantially simpler manner and at the same time in higher yields than are possible by means of existing processes.

This application is a 371 of PCT/EP01/08614 filed Jul. 25, 2001.

The present invention relates to a process for preparing4-methylpyrimidine which is a viable intermediate for producing drugsand crop protection agents.

The preparation of 4-methylpyrimidine is known in principle. Aside froma number of very complicated indirect syntheses from chlorinated4-methylpyrimidines by reduction, processes in which a C₄ component isreacted with an NCN component are particularly suitable for thepreparation.

Bredereck et al. (Org. Synth. Coll. Vol. V, 794, Wiley 1973) describe apracticable process starting from formamide and4,4-dimethoxy-2-butanone, in which 4-methylpyrimidine is obtained in ayield of from 54 to 63%. However, a disadvantage of this process is thata very large excess of formamide (over 6 mol of formamide per mole of4,4-dimethoxy-2-butanone) is required. A portion of this formamidedecomposes in the course of the reaction to carbon monoxide, whichpresents handling problems. Owing to its solubilizing properties, theremainder of the formamide hinders the subsequent extraction of theproduct from water. In addition, the reaction described requires veryhigh temperatures (from 180 to 190° C.), which leads to increasedby-product formation.

The only existing alternative direct synthesis is the reaction describedin DE patent 822 086 of formamidine hydrochloride with the commerciallyunavailable 1,1,3,3-tetramethoxybutane and methanolic HCl.

It is an object of the present invention to provide a process which canbe carried out in a technically simple manner for preparing4-methylpyrimidine, which does not have the disadvantages of the priorart detailed, but instead delivers good yields from industriallyavailable raw materials under comparatively mild reaction conditions.

According to the invention, this object was achieved by reacting a4,4-dialkoxy-2-butanone with a formamidine salt, optionally in thepresence of a solvent or diluent, at temperatures of from 80 to 180° C.In this context, it has surprisingly proven to be the case that4-methylpyrimidine can be obtained with the aid of the process accordingto the invention in a substantially simpler manner and at the same timein higher yields than is possible by means of existing processes.

In the process according to the present invention, a4,4-dialkoxy-2-butanone as a C₄ component is thus reacted with aformamidine salt as an NCN component.

Examples of particularly suitable 4,4-dialkoxy-2-butanones are4,4-dimethoxybutanone and 4,4-diethoxy-2-butanone, and the industriallyreadily available 4,4-dimethoxy-2-butanone is to be regarded asparticularly preferred.

Examples of suitable formamidine salts are appropriate salts ofcarboxylic acids, hydrohalic acids or oxygen acids and in particular theacetate, the hydrochloride and the sulfate. These formamidine salts canbe prepared in a technically simple manner, for example formamidineacetate (cf. DE-B 38 08 767).

These two starting substances can be reacted with or without solvent ordiluent (for example alcohols, esters or carboxylic acids) and also withor without further substances, for example catalysts (in particularacids or acidic salts). However, preference is given to carrying out thereaction without solvent or addition of further substances.

The molar ratio of the 4,4-dialkoxy-2-butanone to formamidine salts ispreferably between 1:2 to 2:1, in particular 1.2:1 to 1:1.2. Thestarting compounds may be initially charged together, although it ispossible without any problem to meter in one of the two startingcomponents during the reaction.

The reaction according to the invention is carried out at temperaturesof from 80 to 180° C., preferably from 110 to 150° C. Alcohol formed,for example methanol or ethanol, can be refluxed. However, in apreferred embodiment, it is continuously removed from the reactionmixture by distillation. The reaction time is generally from 0.5 to 48hours, preferably from 2 to 8 hours.

After reaction is complete, the reaction mixture is preferably cooled,admixed with water and a strong base, for example sodium hydroxidesolution, and the 4-methylpyrimidine is extracted in a known mannerusing an organic solvent (for example t-butyl methyl ether) and the4-methylpyrimidine is purified by distillation after removing thesolvent, the purification preferably being carried out with the aid offractional distillation.

The process according to the invention enables 4-methylpyrimidine to beobtained in a technically simple manner in good yields and highpurities, starting from industrially available starting materials.

The examples which follow are intended to illustrate the presentinvention in detail.

EXAMPLES Example 1

(Comparison According to Bredereck et al)

200 g (1.5 mol) of 4,4-dimethoxy-2-butanone, 375 g (8.3 mol) offormamide, 25 g of ammonium chloride and 12.5 g of water were initiallycharged in a three-neck flask equipped with a column and Liebigcondenser, heated to 185° C. (bath temperature) within 1 hour andmaintained at this temperature over 5 hours. During this time, a liquiddistilled over from the top of the column at a top temperature of from50 to 65° C., and contained methanol, methyl formate and ammonia andreleased carbon monoxide over several days.

The viscous reaction product was admixed with 500 ml of water and 65 gof 50% sodium hydroxide solution and then extracted with t-butyl methylether in a liquid-liquid extractor for 26 hours.

The extract was concentrated and the crude product (71.5 g) wasdistilled through a column to obtain two fractions:

Top 4-methylpyrimidine temperature Weight content Fraction 1 140-142° C.41.5 g 97.5% Fraction 2 142-144° C.  8.5 g 88.3%

The total isolated yield was calculated as 34.0%.

Example 2

(Inventive)

198.2 g (1.5 mol) of 4,4-dimethoxy-2-butanone were initially charged ina three-neck flask equipped with a column and Liebig condenser andheated to 140° C. To this mixture were added in 10 equal portions 141.9g (1.36 mol) of formamidine acetate over the course of one hour. Duringthis time and also during the 4-hour post-reaction time at 140° C., puremethanol distilled off continuously.

The mixture was cooled, admixed with 100 g of water and 65 g of 50%sodium hydroxide solution, and extracted continuously with t-butylmethyl ether for a total of 20 hours.

The extract was concentrated and the crude product (101.8 g) distilledthrough a column to obtain two fractions:

Top 4-methylpyrimidine temperature Weight content Fraction 1 140-142° C.68.5 g 96.1% Fraction 2 142-144° C. 14.0 g 94.4%

The total isolated yield was calculated as 61.8%.

Example 3

(Inventive)

208.2 g (2.0 mol) of formamidine acetate was suspended in 100 g of pureacetic acid and heated to 80° C. Within 2 hours, 198.2 g (1.5 mol) of4,4-dimethoxy-2-butanone were metered in at 80° C. and subsequentlyheated to 150° C. (bath temperature) for a further 3 hours. Over theentire reaction time, methanol formed was continuously distilled off.

The mixture was cooled, admixed with 300 g of water and 165.5 g of 50%sodium hydroxide solution and extracted continuously with t-butyl methylether for a total of 20 hours.

The extract was concentrated and the crude product (90.3 g) distilledthrough a column. 72.8 g of 4-methylpyrimidine having a purity of 95.3%were obtained. The yield was 49.0%.

1. A process for preparing 4-methylpyrimidine comprising reacting a4,4-dialkoxy-2-butanone with a formamidine salt, optionally in thepresence of a solvent or diluent, at temperatures of from 80 to 180° C.2. The process of claim 1, wherein said 4,4-dialkoxy-2butanone is4,4-dimethoxy-2-butanone.
 3. The process of claim 1, wherein saidformamidine salt is formamidine acetate.
 4. The process of claim 1,wherein the reaction is carried out at a temperature of from 110 to 150°C.
 5. The process of claim 1, wherein the moltar ratio of4,4-dialkoxy-2-butanone to formamidine salt is from 1:2 to 2:1.
 6. Theprocess of claim 1, wherein the molar ratio of 4,4-dialkoxy-2-butanoneto formadine salt is from 1.2:1 to 1:1.2.
 7. The process of claim 1,wherein alcohol formed during the reaction is continuously distilledoff.
 8. The process of claim 1, wherein after the reaction is completed,the reaction mixture is admixed with water and a strong base solutionand 4-methylpyrimidine is extracted with an organic solvent andsubsequently purified by distillation.
 9. The process of claim 8,wherein said distillation is fractional distillation.